WO2024257775A1 - 化合物又はその塩及びその製造方法、組成物、過酸化水素除去剤、並びに、細胞毒性抑制剤 - Google Patents

化合物又はその塩及びその製造方法、組成物、過酸化水素除去剤、並びに、細胞毒性抑制剤 Download PDF

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WO2024257775A1
WO2024257775A1 PCT/JP2024/021265 JP2024021265W WO2024257775A1 WO 2024257775 A1 WO2024257775 A1 WO 2024257775A1 JP 2024021265 W JP2024021265 W JP 2024021265W WO 2024257775 A1 WO2024257775 A1 WO 2024257775A1
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mass
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compound
hydrogen peroxide
salt
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French (fr)
Japanese (ja)
Inventor
淳 松本
邦男 小坂
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Nagase and Co Ltd
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Nagase and Co Ltd
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Priority to JP2025519185A priority Critical patent/JP7755772B2/ja
Priority to KR1020267000808A priority patent/KR20260022421A/ko
Priority to CN202480039105.XA priority patent/CN121311472A/zh
Priority to EP24823390.0A priority patent/EP4729511A1/en
Publication of WO2024257775A1 publication Critical patent/WO2024257775A1/ja
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/84—Sulfur atoms

Definitions

  • the present invention relates to a novel ergothioneine derivative and a method for producing the same, a composition containing the derivative, a hydrogen peroxide remover, and a cytotoxicity inhibitor, etc.
  • L-ergothioneine (sometimes referred to as "EGT" in this specification) is a type of sulfur-containing amino acid that is known to have a variety of physiological activities.
  • compositions that have been known to date that have the effect of removing hydrogen peroxide include, for example, antioxidant functional water containing fine bubbles (see, for example, Patent Document 1).
  • compositions that have been known to date that have the effect of inhibiting cytotoxicity include, for example, intracellular thioredoxin system activators that contain hinokitiol (see, for example, Patent Document 2).
  • the present invention aims to provide a novel ergothioneine derivative and a method for producing the same, a composition containing the derivative, a hydrogen peroxide remover, and a cytotoxicity inhibitor, etc.
  • the present invention provides the compounds or salts thereof shown below (hereinafter, sometimes referred to as “compounds” or “compounds, etc.”).
  • Item 1 A compound represented by the following formula (1) or a salt thereof:
  • the present invention also provides the compositions described below.
  • Item 2 A composition comprising the compound according to item 1 or a salt thereof.
  • the present invention also provides the following hydrogen peroxide remover.
  • Item 3 Item 10. A hydrogen peroxide scavenger comprising the compound or a salt thereof according to item 1.
  • Item 4. The hydrogen peroxide remover according to Item 3, wherein the compound or a salt thereof is used at a concentration of 0.04 ⁇ M or more.
  • the present invention also provides the following cytotoxicity inhibitors:
  • Item 5 A cytotoxicity inhibitor comprising the compound or a salt thereof according to Item 1, which is used in the presence of hydrogen peroxide.
  • the present invention also relates to the manufacturing method described below.
  • Item 6 A method for producing a compound represented by the following formula (1) or a salt thereof, comprising: a step (1) of heat-treating an aqueous solution of L-ergothioneine at 60° C. or higher for 24 hours or longer.
  • the compound of the present invention or its salt, or a composition containing the compound can be suitably used, for example, as a hydrogen peroxide remover or a cytotoxicity inhibitor.
  • the hydrogen peroxide remover of the present invention can also, for example, effectively remove hydrogen peroxide.
  • the cytotoxicity inhibitor of the present invention can, for example, reduce cytotoxicity caused by hydrogen peroxide in a culture medium.
  • the above compound or a salt thereof can be easily obtained.
  • FIG. 1 is a graph showing the results of HPLC analysis after 96 hours of heat treatment in Example 1.
  • FIG. 2 is a graph showing the measurement results of liquid chromatography high resolution mass spectrometry (LC-HRMS) in Example 1.
  • FIG. 3 is a graph showing the evaluation results of the amount of remaining hydrogen peroxide in Example 2.
  • FIG. 4 is a table showing the evaluation results of the amount of remaining hydrogen peroxide in Example 2.
  • FIG. 5 is a photograph showing the evaluation results of the cytotoxicity of hydrogen peroxide on HEK293 cells in Example 3.
  • FIG. 6 is a graph showing the evaluation results of hydrogen peroxide cytotoxicity against HEK293 cells in Example 3.
  • FIG. 7 is a graph showing the evaluation results of hydrogen peroxide cytotoxicity against HEK293 cells in Example 3.
  • FIG. 8 is a photograph showing the evaluation results of the cytotoxicity of hydrogen peroxide on HEK293 cells in Example 3.
  • the above compound is a type of oxidized dimer of L-ergothioneine.
  • the salts of the above compounds may be intramolecular salts in these structures and may contain other counter cations and/or counter anions.
  • the salt of the compound may be, for example, a pharmacologically or physiologically acceptable salt.
  • the salt is not particularly limited, but specific examples include organic acid salts, inorganic acid salts, organic bases, and inorganic bases.
  • organic acid salts include monocarboxylates such as acetates, trifluoroacetates, butyrates, palmitates, and stearates; polycarboxylates such as fumarates, maleates, succinates, and malonates; oxycarboxylates such as lactates, tartrates, and citrates; and organic sulfonates such as toluenesulfonates such as methanesulfonates and tosylates.
  • Examples of inorganic acid salts include hydrochlorides, sulfates, nitrates, hydrobromides, and phosphates.
  • Examples of salts with organic bases include salts with organic amines such as methylamine, triethylamine, triethanolamine, diethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, and ethylenediamine.
  • Examples of salts with inorganic bases include ammonium salts; salts with alkali metals such as sodium or potassium, alkaline earth metals such as calcium or magnesium, and metals such as aluminum. These salts may be used alone or in any combination of two or more.
  • the above salts may include solvates or hydrates of the salt.
  • the above compound (1) can also be obtained by known methods such as synthesis, extraction, and fermentation.
  • L-ergothioneine can be appropriately oxidized.
  • L-ergothioneine can be heated at high temperature for a long period of time, and then separated and purified by high performance liquid chromatography or the like.
  • L-ergothioneine can be synthesized by heating an aqueous solution of L-ergothioneine under basic conditions, and it is preferable to use a method including step (1) of heating at 60°C or higher for 24 hours or more. It is even more preferable to use a method including step (1) of heating at 60°C or higher and pH 9-11 for 24 hours or more.
  • step (1) by performing step (1) at, for example, 80°C or higher, it is possible to synthesize a solution of L-ergothioneine at a concentration of, for example, 1500 mM as an aqueous solution.
  • the concentration of the L-ergothioneine aqueous solution is, for example, preferably 1 mM or more, more preferably 10 mM or more, and even more preferably 100 mM or more, depending on the purpose and application of use.
  • the concentration of the L-ergothioneine aqueous solution can be, for example, 2 M or less, 1.8 M or less, 1.5 M or less, 1.3 M or less, etc., depending on the purpose and application of use.
  • composition of the present invention contains the above-mentioned compound (1).
  • the compound (1) may be contained alone or in combination of two or more kinds.
  • the content of the above compound (1) is appropriately adjusted depending on the use of the composition, the type and content of other components, etc., and is not limited, but can be, for example, 0.000001 mass% or more relative to the total amount of the composition, examples of which include 0.0000015 mass% or more, 0.000005 mass% or more, 0.00001 mass% or more, 0.00005 mass% or more, 0.0001 mass% or more, 0.0005 mass% or more, 0.001 mass% or more, etc.
  • the content of the compound (1) can be, for example, 99.999% by mass or less, 99.9% by mass or less, 99.5% by mass or less, 99% by mass or less, 98.5% by mass or less, 98% by mass or less, 80% by mass or less, 70% by mass or less, 60% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, 10% by mass or less, 5% by mass or less, 1% by mass or less, etc., based on the total amount of the composition.
  • the content of the compound (1) when prepared as a liquid composition or liquid preparation, can be, for example, 80% by mass or less, 70% by mass or less, 60% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, 10% by mass or less, 5% by mass or less, 1% by mass or less, etc., based on the total amount of the composition.
  • the above composition may further contain various known components and additives depending on the application of the composition and the types of other components.
  • the above components and additives include excipients, lubricants, binders, and disintegrants; for liquid preparations, solvents, solubilizers, emulsifiers, emulsion stabilizers, thickeners, moisturizers, suspending agents, isotonicity agents, buffers, soothing agents, preservatives, antioxidants, colorants, sweeteners, and flavors. These may be used alone or in combination of two or more.
  • the hydrogen peroxide remover of the present invention contains the above-mentioned compound (1).
  • the compound (1) may be contained alone or in combination of two or more kinds.
  • the hydrogen peroxide remover of the present invention has the above-mentioned configuration and can, for example, effectively remove hydrogen peroxide.
  • the content of the above compound (1) (the total amount when multiple types are present) is appropriately adjusted depending on the application of the hydrogen peroxide remover, the types and contents of other components, etc., and is not limited, and can be, for example, 0.000001 mass% or more relative to the total amount of the hydrogen peroxide remover, such as 0.0000015 mass% or more, 0.000005 mass% or more, 0.00001 mass% or more, 0.00005 mass% or more, 0.0001 mass% or more, 0.0005 mass% or more, 0.001 mass% or more, etc.
  • the content of the above compound can be, for example, 99.999% by mass or less, 99.9% by mass or less, 99.5% by mass or less, 99% by mass or less, 98.5% by mass or less, 98% by mass or less, 80% by mass or less, 70% by mass or less, 60% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, 10% by mass or less, 5% by mass or less, 1% by mass or less, etc., based on the total amount of the hydrogen peroxide remover.
  • the content of compound (1) when prepared as a liquid hydrogen peroxide remover or liquid preparation, can be, for example, 80% by mass or less, 70% by mass or less, 60% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, 10% by mass or less, 5% by mass or less, 1% by mass or less, etc., based on the total amount of the hydrogen peroxide remover.
  • the concentration of the compound (1) may be, for example, 0.01 ⁇ M to 0.1 ⁇ M, 0.02 ⁇ M to 0.08 ⁇ M, 0.03 ⁇ M to 0.06 ⁇ M, or 0.04 ⁇ M to 0.05 ⁇ M, depending on the purpose and application.
  • a preferred example is when the compound (1) is used at a concentration of 0.04 ⁇ M or more.
  • the hydrogen peroxide remover may further contain the above-mentioned various known components and additives depending on the application of the hydrogen peroxide remover and the types of other components. These may be used alone or in combination of two or more types.
  • the cytotoxicity inhibitor of the present invention contains the above-mentioned compound (1) and is used in the presence of hydrogen peroxide.
  • Compound (1) may be contained alone or in combination of two or more kinds.
  • the cytotoxicity inhibitor of the present invention has the above-mentioned configuration and can, for example, reduce the cytotoxicity caused by hydrogen peroxide in the culture medium.
  • the content of the above compound (1) (the total amount when multiple types are present) is appropriately adjusted depending on the application of the cytotoxicity inhibitor, the type and content of other components, etc., and is not limited to, for example, 0.000001 mass% or more relative to the total amount of the cytotoxicity inhibitor, examples of which include 0.000005 mass% or more, 0.00001 mass% or more, 0.00005 mass% or more, 0.0001 mass% or more, 0.0005 mass% or more, 0.001 mass% or more, etc.
  • the content of the compound (1) can be, for example, 99.999% by mass or less, 99.9% by mass or less, 99.5% by mass or less, 99% by mass or less, 98.5% by mass or less, 98% by mass or less, 80% by mass or less, 70% by mass or less, 60% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, 10% by mass or less, 5% by mass or less, 1% by mass or less, etc., based on the total amount of the cytotoxicity inhibitor.
  • the content of the compound (1) when prepared as a liquid cytotoxicity inhibitor or liquid preparation, can be, for example, 80% by mass or less, 70% by mass or less, 60% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, 10% by mass or less, 5% by mass or less, 1% by mass or less, etc., based on the total amount of the cytotoxicity inhibitor.
  • the compound or its salt may be used at a concentration of, for example, 0.01 ⁇ M to 10 ⁇ M, 0.1 ⁇ M to 5 ⁇ M, 1 ⁇ M to 3 ⁇ M, etc., depending on the purpose and application.
  • cytotoxicity inhibitors can also be used in combination with the above-mentioned various known components and additives depending on the application of the cytotoxicity inhibitor and the types of other components. These may be used alone or in a mixture of two or more types.
  • Example 1 (Preparation of Compounds) A compound represented by the following formula (1) (hereinafter also referred to as “Compound A” or “EGT-X”) was prepared by the following method.
  • the obtained fraction was concentrated from about 1000 mL to 30 mL using a rotary evaporator (60° C. water bath). It was then freeze-dried to obtain 108 mg of a yellow powder of compound A. The obtained compound A was redissolved in D 2 O and subjected to NMR analysis.
  • LC-HRMS liquid chromatography high resolution mass spectrometry
  • Example 2 (Hydrogen peroxide removal evaluation) The obtained compound A (EGT-X) was diluted in two-fold increments from 10 ⁇ M with the buffer included in the kit (OxiSelect hydrogen peroxide assay kit (manufactured by CELL BIOLABS)), and 25 ⁇ L of each was added to a 96-well plate. Hydrogen peroxide was also diluted with the buffer included in the kit to 4 ⁇ M, and 25 ⁇ L of each was added to the 96-well plate. Furthermore, a blank was prepared under the same conditions except that hydrogen peroxide was not added.
  • Example 3 Cytotoxicity inhibition evaluation To evaluate cytotoxicity inhibition, the cytotoxicity of hydrogen peroxide against HEK293 cells was evaluated.
  • HEK293 cells 15x10 4 cells/mL
  • DMEM Dulbecco's modified Eagle medium
  • FBS fetal bovine serum
  • 100 ⁇ L each of DMEM alone or DMEM containing hydrogen peroxide was added to the wells to give hydrogen peroxide concentrations of 0, 0.001, 0.002, and 0.004%.
  • the cell viability was observed after 24 hours of exposure to hydrogen peroxide.
  • 50 ⁇ L of a 1:1 mixture of DMEM containing 5% FBS and WST-1Premix (TAKARA Bio) was added and incubated in a 5% CO 2 incubator for 30 minutes. The absorbance at 450 nm was measured.
  • a blank was measured under the same conditions as above except that no cells were used, and the cell viability was calculated by subtracting the blank value from the above result (FIGS. 5 and 6).
  • a suspension of HEK293 cells (15x10 4 cells/mL, 5% FBS-DMEM) was added to a 96-well plate at 100 ⁇ L each. After 24 hours, EGT-X dissolved in DMEM and hydrogen peroxide dissolved in DMEM were added to the plate at 50 ⁇ L each, and the hydrogen peroxide concentration was set to 0 for the control, 0.0015% for the others, and the EGT-X concentration was set to the concentration shown in the figures (FIGS. 5 and 6).

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PCT/JP2024/021265 2023-06-15 2024-06-12 化合物又はその塩及びその製造方法、組成物、過酸化水素除去剤、並びに、細胞毒性抑制剤 Ceased WO2024257775A1 (ja)

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JP2025519185A JP7755772B2 (ja) 2023-06-15 2024-06-12 化合物又はその塩及びその製造方法、組成物、過酸化水素除去剤、並びに、細胞毒性抑制剤
KR1020267000808A KR20260022421A (ko) 2023-06-15 2024-06-12 화합물 또는 그의 염 및 그의 제조 방법, 조성물, 과산화수소 제거제, 그리고 세포 독성 억제제
CN202480039105.XA CN121311472A (zh) 2023-06-15 2024-06-12 化合物或其盐及其制造方法、组合物、过氧化氢清除剂以及细胞毒性抑制剂
EP24823390.0A EP4729511A1 (en) 2023-06-15 2024-06-12 Compound or salt thereof and method for producing same, composition, hydrogen peroxide remover, and cytotoxicity inhibitor

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007300916A (ja) * 2006-04-10 2007-11-22 Manabu Nukina エルゴチオネインの製造方法
JP2008156320A (ja) 2006-12-26 2008-07-10 Hydrox Kk 抗酸化性機能水
CN109091422A (zh) * 2018-08-01 2018-12-28 上海应用技术大学 含榆黄菇提取液的化妆品及其制备方法
CN109293572A (zh) * 2018-09-26 2019-02-01 上海市农业科学院 一种提取榆黄菇中麦角硫因与多糖的方法
JP2020103100A (ja) 2018-12-27 2020-07-09 小林製薬株式会社 細胞内の抗酸化機能亢進剤
WO2021177397A1 (ja) * 2020-03-04 2021-09-10 長瀬産業株式会社 Ｌ－エルゴチオネイン含有組成物

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007300916A (ja) * 2006-04-10 2007-11-22 Manabu Nukina エルゴチオネインの製造方法
JP2008156320A (ja) 2006-12-26 2008-07-10 Hydrox Kk 抗酸化性機能水
CN109091422A (zh) * 2018-08-01 2018-12-28 上海应用技术大学 含榆黄菇提取液的化妆品及其制备方法
CN109293572A (zh) * 2018-09-26 2019-02-01 上海市农业科学院 一种提取榆黄菇中麦角硫因与多糖的方法
JP2020103100A (ja) 2018-12-27 2020-07-09 小林製薬株式会社 細胞内の抗酸化機能亢進剤
WO2021177397A1 (ja) * 2020-03-04 2021-09-10 長瀬産業株式会社 Ｌ－エルゴチオネイン含有組成物

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* Cited by examiner, † Cited by third party
Title
SERVILLO LUIGI, CASTALDO DOMENICO, CASALE ROSARIO, D’ONOFRIO NUNZIA, GIOVANE ALFONSO, CAUTELA DOMENICO, BALESTRIERI MARIA LUISA: "An uncommon redox behavior sheds light on the cellular antioxidant properties of ergothioneine", FREE RADICAL BIOLOGY & MEDICINE, vol. 79, 1 February 2015 (2015-02-01), US , pages 228 - 236, XP093249262, ISSN: 0891-5849, DOI: 10.1016/j.freeradbiomed.2014.11.017 *

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EP4729511A1 (en) 2026-04-22
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KR20260022421A (ko) 2026-02-19
CN121311472A (zh) 2026-01-09

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